Description: (Taken directly from the application) Understanding the molecular and cellular events which lead to normal bone formation is an essential prerequisite for understanding the etiology of skeletal disorders in man. Further, it may provide insights which will permit the design of new therapeutic approaches for treating pathological or accidental damage to the skeleton. Development of the endochondral skeleton is regulated by cell-cell interactions mediated by members of several signaling factors including Wnts, transforming growth factor-beta (TGF-B) superfamily members, Hedgehogs, PTHrP, and fibroblast growth factors (FGFs). The goal of this application is to establish the role of several key secreted regulators of cartilage morphogenesis and to examine how these factors interact in cartilage and bone development. This will be done in genetic studies which utilize mice carrying either null mutations or gain of function transgenes in signaling factors, their potential regulators or their potential targets. Specific Aim 1 will determine the extent to which Ihh regulates cartilage morphogenesis through the PTHrP pathway and will address the cell autonomous and potential non-cell autonomous action of Ihh signaling in bone and cartilage development. Specific Aim 2 sets out to test whether Ihh may mediate the growth-regulating action of Hoxa-11 and Hoxd-11 in the ulna and radius. Specific Aim 3 examines the possible genetic interactions between Noggin, a putative BMP antagonist, and BMP4, in forming the axial skeleton. Specific Aim 4 addresses the molecular mechanisms by which Wnt 5a regulates proximo-distal outgrowth of the limb and growth of proximal cartilage elements.